CHICAGO (FRONTLINE MEDICAL NEWS) – Liquid biopsy, the testing of the blood for circulating tumor DNA (ctDNA), identified cancer mutations useful as biomarkers in 85% of all advanced cancer cases in the largest-ever genomic analysis performed using such technology.

In nearly half of those (49%), the biomarkers were associated with an approved targeted drug, Philip C. Mack, Ph.D., reported at the annual meeting of the American Society of Clinical Oncology.

The patterns of genetic changes detected in the 17,628 blood specimens analyzed for the study using a highly sensitive next-generation sequencing technique closely mirrored those identified using traditional tumor biopsies, suggesting that liquid biopsy provides a non-invasive alternative to tissue biopsy in certain cases, Dr. Mack , professor and director of molecular pharmacology at the University of California, Davis Comprehensive Cancer Center, said during a press briefing at the meeting.

Overall, taking into account FDA-approved drugs and eligibility for clinical trials, the ctDNA testing revealed a possible treatment option for 63.6% of the 15,191 patients who provided samples.

Further, the commercially available liquid biopsy assay used in the study (Guardant360) identified the presence of resistance alterations that could guide new therapy in patients with tumors that acquire resistance to an effective treatment, he said, noting that these resistance mutations are not typically present at the time of initial tissue-biopsy.

Of the patients included in the study, 37% had lung cancer, 14% had breast cancer, 10% had colorectal cancer, and 39% had other cancers. A comparison of genomic changes in ctDNA in 398 patients with available tumor tissue genetic test results showed that when ctDNA was positive for key abnormalities associated with tumor growth, the same mutations were reported in tissue 94% to 100% of the time.

Most of the ctDNA alterations were found at very low levels – with half occurring at a frequency below 0.4% of the total DNA in circulation; even at such low levels, the accuracy of the liquid biopsy assay remained high, Dr. Mack noted.

The ctDNA findings also compared well with those from publicly available population-scale sequencing projects, most notably the Cancer Genome Atlas, he said.

Alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity.

Interest in comprehensive tumor genetic profiling to guide patients toward appropriate targeted therapies based on the molecular makeup of their tumors has been increasing, and the current findings underscore its potential value. Advantages of plasma testing include ease of use in any clinic setting, avoidance of biopsy-related complications, ability to monitor changes in disease over time, potential identification of mutations in metastatic lesions not observed in the original tumor biopsy (as genetic changes driving tumor growth often differ in different parts of the tumor), and the opportunity to identify treatment-induced resistance mechanisms, Dr. Mack said.

Additionally, liquid biopsy could be particularly helpful in cases involving tumors for which a traditional biopsy is difficult to obtain.

In fact, the clinical utility of liquid biopsy was evident among 362 lung cancer cases in the study. Tissue was insufficient for traditional biopsy in 63% of the cases, and ctDNA testing identified key genetic mutations at frequencies consistent with their prevalence in the published literature. Thus, ctDNA provided these patients with their only source of an actionable target, Dr. Mack noted.

As for whether liquid biopsy could or should replace tissue biopsy, he explained that it should be viewed more as an additional tool.

“I think there is always going to be a role for tissue-based biopsy,” he said, explaining that a tissue biopsy allows the pathologist to assess the morphological features of the cancer to diagnose it and determine what the tumor type is and where it originated. “That will always be required.”

Leftover tissue should be used for mutational testing, and this is the gold standard. It is in cases when the tissue is of insufficient quality or quantity to allow a broader array of testing that liquid biopsy can provide a complementary source of information, he said.

Further, while it would be ideal to have biopsies of any progressing lesion in a patient who initially had a great response to treatment, that is not feasible, he said.

“So probably, the biggest role for plasma analysis will be occurring down the road as patients are progressing on therapies, as their tumors are evolving, as a way to monitor progression of those cancers,” he said.

Dr. Sumanta Kumar Pal , an ASCO spokesperson and a panel member at the press briefing, noted that “the data that Dr. Mack reported provides key insights into the feasibility of the so-called liquid biopsy.”

“We’re increasingly using genomic data from day-to-day in our clinics to guide therapies,” he said, reiterating that tests such as this provide a useful alternative to tissue-based testing, particularly for the many patients in clinics who have tumors that are challenging to access, such as tumors on bone or near the brain.

“The authors have demonstrated not only the feasibility of the test in detecting alterations, but that the results are often potentially actionable as well … As oncologists obtain this assay, it’s important to keep in mind trials such as the ASCO-led TAPUR study. TAPUR can potentially link patients with selected genomic alterations to relevant therapies that would otherwise be challenging to access,” he said.

Dr. Pal also noted that there are several other blood-based genomic tests emerging, and it will be important to “rigorously define which of these platforms deliver optimal results.”

Going forward, Dr. Mack and his colleagues will be working to increase the sensitivity of the Gaurdant360 assay to detect mutations at extremely low ctDNA level, as some tumors – glioblastomas, for example – diminish the ability to detect ctDNA. Improved sensitivity could also enable the use of the assay in earlier-stage cancers, he said.

This study was supported by funding from Guardant Health.


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